Vortioxetine Pyroglutamate

ABSTRACT

The present invention provides vortioxetine pyroglutamate salt and pharmaceutical compositions comprising said salt.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to Danish Application No. PA201500284,filed May 13, 2015, which is herein incorporated by reference.

TECHNICAL FIELD

The present invention relates to vortioxetine pyroglutamate and its usein pharmaceutical compositions.

BACKGROUND

International patent applications including WO 03/029232 and WO2007/144005 disclose the compound1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine andpharmaceutically acceptable salts thereof. WHO has since published thatvortioxetine is the recommended International Non-proprietary Name (INN)for 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. Vortioxetinewas formerly referred to in the literature as Lu AA21004. In Septemberand December 2013 FDA and EMA, respectively, approved vortioxetine forthe treatment of major depressive disorder/major depressive episodeunder the trade name Brintellix™. Of particular interest, vortioxetinehas also shown effect in elderly suffering from recurrent majordepressive disorder [Int. Clin. Psychopharm., 27, 215-227, 2012].

Vortioxetine is an antagonist on the 5-HT₃, 5-HT₇ and 5-HT_(1D)receptors, an agonist on the 5-HT_(1A) receptor and a partial agonist onthe 5-HT_(1B) receptor and an inhibitor of the serotonin transporter.Additionally, vortioxetine has demonstrated to enhance the levels of theneurotransmitters serotonin, noradrenalin, dopamine, acetylcholine andhistamine in specific areas of the brain. All of these activities areconsidered to be of clinical relevance and potentially involved in themechanism of action of the compound [J.Med.Chem., 54, 3206-3221, 2011;Eur. Neuropshycopharmacol., 18(suppl 4), S321, 2008; Eur.Neuropshycopharmacol., 21(suppl 4), S407-408, 2011; Int. J. PsychiatryClin Pract. 5, 47, 2012]. The pharmacological profile gives reason tobelieve that vortioxetine may have a pro-cognitive effect. This notionseems to be supported by clinical evidence where vortioxetine has beenshown to have a direct beneficial effect on cognition independent of itsantidepressive effects [Int. Clin. Psychopharm., 27, 215-227, 2012; IntJ neurophychopharm 17, 1557-1567, 2014; Neuropsychopharmacol, 40,2025-2037, 2015.

Vortioxetine is available on the market as film coated instant release(IR) tablets containing 5, 10, 15 and 20 mg vortioxetine as the HBr saltand as an oral drop solution comprising 20 mg/ml vortioxetine as the DLlactate salt.

It is well-established that swallowing tablets and capsules may be aproblem for a significant number of patients, and this may ultimatelylead to lack of compliance with the consequent increased risk ofinadequate treatment response or relapse. Studies have shown that everythird woman and every sixth man report problems with swallowing tablets.Notably, difficulties with swallowing tablets seem to be morewide-spread in the elderly population and amongst children [Pharm WorldSci, 23, 185-188, 2001]. Different technologies have been applied toovercome the problems with swallowing tablets and capsules. For example,alternatives to oral administration may be used, such as parenteral,transdermal, nasal, buccal, sublingual or rectal administration.Alternatively, easy-to-swallow oral administration forms such as oralsolutions, oral dispersible tablets, powders or granules to be sprinkledon food or oral gels may be applied.

Gel compositions for oral administration are an attractive alternativeto tablets and capsules because they combine the ease and simplicity oforal administration with little or no resistance to swallowing. Due tothe inherent decreased stability of pharmaceutical products in liquid orsemi-solid (e.g. gel form) compositions, gel compositions are oftenprovided as dry powders which are to be mixed with a liquid, typicallywater or saliva, immediately prior to use to form the gel. U.S. Pat. No.6,709,678 discloses a pharmaceutical composition comprising an activeingredient in combination with hydratable polymers, such as alginates orcarboxymethylcellulose which upon contact with saliva forms a gel in themouth. WO 01/76610 discloses a composition comprising vitamin D andstarch derivatives which upon mixing with water forms a pudding-likegelled suspension. WO 2005/107713 discloses a composition comprising anactive ingredient together with gellan gum which upon addition of waterswells or gels to have a texture similar to that of a soft pudding. Suchadministration form has been developed for commercial use under thetrade name Parvulet™. Parvulet™ comes as a spoon preloaded with activeingredient and a gelling polymer and wrapped in foil. The user unwrapsthe spoon and adds water to form the gel. It is a common characteristicof these technologies that gelling or swelling is obtained by use ofgelling polymers. The application of additional excipients in anypharmaceutical composition is always problematic because it increasesthe risk of lack of compatibility between the active ingredient and theexcipients or between excipients.

One aim of the present invention is to provide vortioxetine salts whichcan be administered as an oral gel without the need for gellingpolymers.

WO 2011/023194 and WO 2011/136376 disclose enteric coated (EC)formulations comprising vortioxetine. One aim of the present inventionis to provide enteric coated formulations with superior pharmacokineticproperties.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found that a particular acidaddition salt of vortioxetine, namely vortioxetine pyroglutamate in itsvarious forms in aqueous solution forms a gel in the presence of a salt.Accordingly, in one embodiment, the invention relates to vortioxetinepyroglutamate.

In one embodiment, the invention relates to vortioxetine pyroglutamatefor use in therapy.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising vortioxetine pyroglutamate.

In one embodiment, the invention relates to a gel composition comprisingvortioxetine pyroglutamate, a salt and water.

In one embodiment, the invention relates to a method for preparing a gelsaid method comprising the steps of mixing vortioxetine pyroglutamate, asalt and an aqueous solution.

In one embodiment, the invention relates to the use of vortioxetinepyroglutamate in the manufacture of a medicament for the treatment of aCNS disease.

In one embodiment, the invention relates to vortioxetine pyroglutamatefor use in a method for the treatment of a CNS disease.

In one embodiment, the invention relates to a method for treating a CNSdisease, the method comprising administering a therapeutically effectiveamount of vortioxetine pyroglutamate to a patient in need thereof.

In one embodiment, the invention relates to a method for treating a CNSdisease, the method comprising administering a therapeutically effectiveamount of a gel composition of the present invention to a patient inneed thereof.

FIGURES

FIG. 1: X-ray Powder Diffraction (XRPD) spectrum of vortioxetine(L)-pyroglutamate.

FIG. 2: Thermogravimetric Analysis (TGA) thermogram of vortioxetine(L)-pyroglutamate.

FIG. 3: Differential Scanning calorimetry (DCS) of vortioxetine(L)-pyroglutamate.

FIG. 4: Dynamic Vapour Sorption (DVS) spectrum for vortioxetine(L)-pyroglutamate. (—) Change in mass (%) relative to dry state. (- - -)Target relative humidity (%).

FIG. 5: X-ray Powder Diffraction spectrum of vortioxetine(DL)-pyroglutamate MH.

FIG. 6: Differential Scanning calorimetry of vortioxetine(DL)-pyroglutamate MH.

FIG. 7: Thermogravimetric Analysis thermogram of vortioxetine(DL)-pyroglutamate MH.

FIG. 8: Dynamic Vapour Sorption spectrum for vortioxetine(DL)-pyroglutamate MH. (—) Change in mass (%) relative to dry state.(- - -) Target relative humidity (%).

FIG. 9: X-ray Powder Diffraction spectrum of vortioxetine(DL)-pyroglutamate α-form.

FIG. 10: Differential Scanning calorimetry of vortioxetine(DL)-pyroglutamate α-form.

FIG. 11: Thermogravimetric Analysis thermogram of vortioxetine(DL)-pyroglutamate α-form.

FIG. 12: Dynamic Vapour Sorption spectrum for vortioxetine(DL)-pyroglutamate α-form. (—) Change in mass (%) relative to dry state.(- - -): Target relative humidity (%).

FIG. 13: Plasma concentration-time profiles for vortioxetine in human.X-axis is time in hours post-dosing. Y-axis is plasma concentration inng/ml. • IR (20 mg); Δ pH 5.5 (20 mg); ▪ pH 6.0 (20 mg); □ pH 7.0 (20mg)

FIG. 14: Plasma-concentration profiles for vortioxetine in dogs. X-axisis time in hours post-dosing. Y-axis is plasma concentration in ng/ml. •20 mg solution; ⋄ 20 mg EC HBr; □20 mg IR HBr; ▴ 20 mg EC pyroglutamate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pyroglutamate salts of vortioxetine.Vortioxetine is commercially available or can be synthesised asdisclosed in e.g. WO 03/029232, WO 2007/144005 or WO 2014/128207. Themolecular structure of vortioxetine is depicted below.

The pyroglutamate salts of the present invention may be obtained in areaction between vortioxetine free base and pyroglutamic acid followedby precipitation, as shown in the examples.

Pyroglutamic acid, which is also known as 5-oxoproline and pidolic acid,is formed when the amino group and the side-chain carboxylic acid ofglutamic acid cyclize to form a lactam, as shown in the figure below

As indicated by the *, pyroglutamate contains an asymmetric carbon atomand pyroglutamate therefore exists in three forms, i.e. DL (the racemicform) and D and L (the two enantiomeric) forms. The physical propertiesof vortioxetine pyroglutamate salts may in principle depend on whetherthe counter ion is pyroglutamate in its racemic form or either of itsenantiomeric forms. However, as shown in the examples, bothDL-pyroglutamate and L-pyroglutamate vortioxetine salts can form the gelcompositions of the present invention. Since vortioxetine itself doesnot contain an asymmetric carbon atom and therefore does not exist inenantiomeric forms, vortioxetine L-pyroglutamate and vortioxetineD-pyroglutamate have identical physical properties, including thegelling properties observed by the inventors. Therefore, the inventionprovides vortioxetine pyroglutamate and uses thereof as described hereinwherein pyroglutamate is DL-pyroglutamate, D-pyroglutamate orL-pyroglutamate or any mixture thereof.

Both DL- and L-pyroglutamic acid form 1:1 salt with vortioxetine. Asevidenced by the XRPD reflections shown in the examples, these salts arecrystalline and both hydrated and anhydrous forms exist. However, asvortioxetine pyroglutamate is dissolved prior to or as part of the gelformation, the gel-forming property of vortioxetine pyroglutamate isunlikely to depend on a particular crystalline form of vortioxetinepyroglutamate.

In one embodiment, the invention relates to vortioxetine D-pyroglutamateor L-pyroglutamate with XRPD reflections at 10.72, 12.14, 16.22 and18.59 (° 2θ); such as 10.72, 12.14, 16.05, 16.22, 17.53, 17.70, 18.45and 18.59 (° 2θ), such as 7.02, 10.72, 12.14, 14.45, 14.61, 15.56,16.05, 16.22, 17.53, 17.70, 18.45 and 18.59 (° 2θ). All values are ±01°2θ. In one embodiment, the invention relates to vortioxetineD-pyroglutamate or L-pyroglutamate with XRPD reflection as shown in FIG.1.

In one embodiment, the invention relates to vortioxetine(DL)-pyroglutamate MH (i.e. MonoHydrate) with XRPD reflections at 6.16,9.25, 17.68 and 18.12 (° 2θ), such as at 6.16, 9.25, 14.61, 15.02,15.88, 16.33, 17.68 and 18.12 (° 2θ), such as at 6.16, 9.25, 9.38,12.10, 14.03, 14.61, 15.02, 15.88, 16.33, 16.91, 17.68 and 18.12 (° 2θ).All values are ±0.1 ° 2θ. In one embodiment, the invention relates tovortioxetine (DL)-pyroglutamate MH with XRPD reflection as shown in FIG.5.

In one embodiment, the invention relates to vortioxetine(DL)-pyroglutamate α-form with XRPD reflections at 14.27, 15.75, 17.06and 18.59 (° 2θ), such as at 7.42, 10.78, 13.58, 14.27, 14.60, 15.75,17.06 and 18.59(° 2θ), such as at 7.42, 10.78, 13.58, 13.99, 14.27,14.60, 15.75, 15.90, 16.89, 17.06, 17.87 and 18.59 (° 2θ). All valuesare ±0.1 ° 2θ. In one embodiment, the invention relates to vortioxetine(DL)-pyroglutamate α-form with XRPD reflection as shown in FIG. 9.

As shown in the examples, the aqueous solubility of vortioxetinepyroglutamate is markedly higher than that of any known vortioxetinesalt. The solubility of vortioxetine DL-pyroglutamate MH andvortioxetine DL-pyroglutamate α-form is at least 278 mg/ml, andsolubility of vortioxetine D-pyroglutamate or vortioxetineL-pyroglutamate is 225 mg/ml. These solubility values are determined inwater at approximately 20° C. This is to be compared with solubilitydata for known vortioxetine salts as depicted in the table below

Salt Solubility (mg/ml) Reference Free base 0.1 WO 2007/144005 HBrα-form 2 WO 2007/144005 HBr β-form 1.2 WO 2007/144005 HBr γ-form NA WO2007/144005 HBr hydrate NA WO 2007/144005 HBr ethyl acetate solvate NAWO 2007/144005 HCl 3 WO 2007/144005 HCl mono hydrate 2 WO 2007/144005Mesylate >45 WO 2007/144005 Fumerate 0.4 WO 2007/144005 Maleate 1 WO2007/144005 Meso-tartrate 0.7 WO 2007/144005 L-tartrate 0.4 WO2007/144005 D-tartrate 0.4 WO 2007/144005 Sulphate 0.1 WO 2007/144005Phosphate 1 WO 2007/144005 Nitrate 0.8 WO 2007/144005 HBr with XRPDreflections 3-3.8 WO 2014/044721 at 5.5, 14.8, 16.7 and 20.0(Calculated) (°2θ) L-lactate Monohydrate2 26 WO 2010/121621 DL-lactateβ-form 8 WO 2010/121621

It is evident that vortioxetine pyroglutamate has unparalleledsolubility which is ˜5 times more soluble than the second most solublesalt (mesylate) and ˜200 and ˜25 times more soluble than the marketedsalts (HBr and DL-lactate). This high solubility is beneficial ifvortioxetine is to be administered or sold in e.g. liquid formulationsat high concentrations, such as infusion concentrates and oral drops.

In one embodiment, the invention relates to vortioxetine pyroglutamatefor use in therapy.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising vortioxetine pyroglutamate. A pharmaceutical formulation ofthe invention may be prepared by conventional methods in the art.Tablets may be prepared by mixing the active ingredient with ordinarycarriers and/or diluents and subsequently compressing the mixture in aconventional tabletting machine. Examples of carriers or diluentscomprise: anhydrous calcium hydrogen phosphate, PVP, PVP-VA co-polymers,microcrystalline cellulose, sodium starch glycolate, corn starch,mannitol, potato starch, talcum, magnesium stearate, gelatine, lactose,gums, and the like. Any other carriers or additives usually used forsuch purposes such as colourings, flavourings, preservatives etc. may beused provided that they are compatible with the active ingredients.

Solutions for injections may be prepared by dissolving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to desiredvolume, sterilising the solution and filling it in suitable ampules orvials. Any suitable additive conventionally used in the art may beadded, such as tonicity agents, preservatives, antioxidants, etc.

A pharmaceutical composition of the present invention may beadministered by any suitable route, for example orally in the form oftablets, capsules, powders, syrups, etc., or parenterally in the form ofsolutions for injection. For preparing such compositions, methods wellknown in the art may be used, and pharmaceutically acceptable carriers,diluents, excipients or other additives normally used in the art may beused.

Conveniently, vortioxetine pyroglutamate is administered in a unitdosage form containing said compounds in an amount of about 1 to 50 mg(as free base). The total daily dose is usually in the range of about1-20 mg, such as about 1 to 10 mg, about 5-10 mg, about 10-20 mg, orabout 10-15 mg of the compound of the invention. Particular mention ismade of daily doses of 5, 10, 15 or 20 mg.

The extreme solubility of vortioxetine pyroglutamate salts render thesesalts useful in the preparation of liquid formulations intended for e.g.infusion concentrates or oral drops. Oral drops is a highly concentratedliquid formulation intended for easy oral administration. When oraldrops are administered, the patient or the care taker measures out apre-determined volume of the oral drops which volume is mixed with aglass of drinkable liquid (water, juice etc), and the patient drinks theliquid. The administration form may be beneficial for e.g. elderlypatients who have difficulties swallowing tablets or capsules.

The concentration of vortioxetine in oral drop formulations isdetermined by the number of drops (i.e. the volume) it is desired tocollect and the amount of vortioxetine it is desired to administer. Itis generally held that measuring out around 5-20 drops is an optimalcompromise between safety/efficacy of the treatment on the one hand andconvenience on the other. If the concentration of vortioxetinepyroglutamate is too high, i.e. if only a low number of drops is to bemeasured out, it may jeopardize safety or efficacy of the treatment.With a low number of drops, one or two drops more or less than desiredwill significantly increase the uncertainty in the dose provided. On theother hand, if the concentration of vortioxetine is too low, the numberof drops to be measured out is high, which is inconvenient for thepatient or the caretaker.

In addition to vortioxetine pyroglutamate, the oral drop formulation ofthe present invention may comprise pharmaceutically acceptable solvents,surface tension modifiers, viscosity modifiers, preservatives,antioxidants, colorants, taste maskers, flavours etc. Examples ofsolvents include water and other solvents, which are miscible with wateror solubilizing agents and suitable for oral purposes. Examples ofsuitable solvents are ethanol, propylene glycol, glycerol, polyethyleneglycols, poloxamers, sorbitol and benzyl alcohol. The aqueous solubilityof the active ingredient may further be enhanced by the addition to thesolution of a pharmaceutically acceptable co-solvent, a cyclodextrin ora derivative thereof.

Surface tension modifiers may be included to adjust the drop number forthe concentrated oral formulations. An example of a surface tensionmodifier is ethanol, which decreases the surface tension and increasesthe drop number.

Viscosity modifiers may be included to adjust the drop velocity for aconcentrated oral formulation. The drop velocity for a formulation to bemeasured out in discrete drops from a container fitted with a dropaggregate should preferably not exceed 2 drops per second. Examples ofviscosity modifiers include ethanol, hydroxyethylcellulose,carboxymethylcellulose sodium, methylcellulose, polyvinyl alcohol,polyvinylpyrrolidone, polyethylene glycol and glycerine.

Preservative agents may be added to prevent the growth of microorganisms such as bacteria, yeasts and fungi in liquid formulations,which are likely to be used repeatedly. Suitable preservatives should bephysicochemical stable and effective in the desired pH range. Examplesof preservative agents include ethanol, methylparaben, propylparaben andbenzyl alcohol.

A drug substance is typically more sensitive to chemical degradation indissolved than in solid form; hence it may be necessary to include anantioxidant in the liquid formulation. Examples of antioxidants includepropyl gallate, ascorbyl palmitate, ascorbic acid, sodium sulphite,citric acid and EDTA.

Colouring agents may be used in some formulations to introduce auniformity of appearance to the product. Some active ingredients mayfurther be very sensitive to light and it may prove necessary to addcolouring agents to the drop formulations to protect them from light andfor the purpose of stabilization. Suitable colouring agents include forexample tartrazine and sunset yellow.

Sweetening agents may mask unpleasant taste associated with someformulations or to achieve a desired taste. Examples of sweeteningagents are glucose, sorbitol, glycerol, acesulfame potassium andneohesperidin dihydrochalcon. The taste may be optimized further by theaddition of one or more flavouring substances. Suitable flavouringsubstances are fruit flavours such as cherry, raspberry, black currant,lemon or strawberry flavour or other flavours such as liquorice, anis,peppermint, caramel etc.

An oral drop formulation of the present invention may comprise

7.2% vortioxetine pyroglutamate (˜5% free base)

0.08% methylparahydroxybenzoate

0.2% propylparahydroxybenzoate

Water q.s. ad 100%.

In one embodiment, the invention relates to a gelable pharmaceuticalcomposition comprising vortioxetine pyroglutamate and a salt. In thepresent context, “gelable” indicates that a composition upon addition ofan aqueous solution, such as water, forms a gel. This dry composition iseasy to store and transport and therefore useful as a marketableproduct. In one embodiment, said pharmaceutical composition comprisesvortioxetine pyroglutamate and a salt in a molar ratio of vortioxetinepyroglutamate:salt between 1:0.1 to 1:100, such as 1:0.5 to 1:50, suchas 1:1 to 1:20. The gelable pharmaceutical composition of the presentinvention does not require gelling polymers in order to form a gel. Inone embodiment, the gelable pharmaceutical composition of the presentinvention does not comprise gelling polymers. In the present context,“does not comprise” s intended to indicate that such polymers are notpresent in an amount that causes gelling of the formulation.

A “gelling polymer” in the present context is a polymer which uponmixing with an aqueous phase, such as water or water with Ca++-ions gelsor swells to form a gel. Examples of gelling polymers include starch,gellan, carboxymethylcellulose, pectin, alginate and gelatine. Moreexamples of gelling polymers can be found, e.g. in Remington: Thescience and Practice of Pharmacy, 21^(st) Edition, Lippincott, Williams& Wilkins, 2005.

In one embodiment, the invention relates to a gelable compositioncomprising vortioxetine pyroglutamate and a salt in a unit dose, whereinsaid unit dose comprises 1 mg-50 mg vortioxetine (as free base), such as1, 5, 10, 15 or 20 mg vortioxetine (as free base).

Without being bound to a specific theory it is speculated that thegel-formation observed by the inventors is the result of the extremesolubility of vortioxetine pyroglutamate and the markedly lowersolubility of other salts. Vortioxetine is initially brought intosolution as the pyroglutamate salt. Eventually, vortioxetine willprecipitate with the anion from the salt; however, a metastable gel isformed first which is sufficiently stable to render the gel useful fororal administration. Therefore, in the present context “salt” isintended to indicate a salt formed in a reaction between apharmaceutically acceptable acid and a pharmaceutically acceptable base.Pharmaceutically acceptable acids include hydrochloride acid,hydrobromide acid, phosphoric acid, nitrous acid, sulphuric acid,benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid,succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid,maleic acid, glutamic acid, pyroglutamic acid, salicylic acid, salicylicacid and sulfonic acids, such as ethanesulfonic acid, toluenesulfonicacid and benzenesulfonic acid. Pharmaceutically acceptable bases includealkali metal bases, such as sodium hydroxide, lithium hydroxide,potassium hydroxide, alkaline earth bases, such as calcium hydroxide andmagnesium hydroxide, and organic bases, such as ammonia, tri-methylamine, tri ethyl amine. Additional examples of useful acids and bases toform pharmaceutically acceptable salts can be found e.g. in Stahl andWermuth (Eds) “Handbook of Pharmaceutical salts. Properties, selection,and use”, Wiley-VCH, 2008. In particular, “salt” is intended to indicatea salt with an anion selected from chloride, bromide, fumerate, maleate,meso-tartrate, L-tartrate, D-tartrate, sulphate, phosphate and nitrate.In particular, “salt” is intended to indicate a salt with a cationselected from sodium, potassium, lithium, calcium, magnesium, ammonium,tri-methyl ammonium and tri-ethyl ammonium. In particular, “salt” isintended to indicate KBr, NaCl or NaBr. For the avoidance of doubt,“salt” does not include vortioxetine pyroglutamate.

In addition to vortioxetine pyroglutamate and a salt, a gelablepharmaceutical composition of the present invention may comprise otheringredients known in pharmaceutical science. Other ingredients mayinclude taste modifiers, such as sweeteners and flavours. Examples ofsweeteners include aspartame, acesulfame potassium, cyclamate,glycerrhizin, lactose, mannitol, cassahrin, sucrose and sucralose.Examples of flavours include ethyl vanillin, menthol, glycyrrhiza,fennel and lemon peel.

In one embodiment, the invention relates to a gel comprisingvortioxetine pyroglutamate, a salt and water. A gel of the presentinvention does not require gelling polymers to form. In one embodiment,a gel of the present invention does not comprise gelling polymers. A gelof the present invention is particularly useful for oral administrationbecause it is easily swallowed compared to other oral administrationforms, in particular tablets and capsules. A gel of the presentinvention may comprise other ingredients known in pharmaceuticalscience, in particular taste modifiers, as discussed above. In thepresent context and in line with the USP definition of a gel, a gel isintended to indicate a semisolid system consisting of either smallorganic particles or large organic molecules interpenetrated by aliquid. A gel thus presents as a coherent, viscous, plastic ornon-disintegrating phase. In practical terms, if vortioxetinepyroglutamate, a salt and an aqueous solution is mixed in a 4 ml vial asdescribed example 1 and the vial, after shaking to allow a viscous phaseto form, can be left upside down for 5 minutes within which said viscousphase essentially maintains its physical shape, and without said viscousphase disintegrates or leaves the vial, a gel is formed. In oneembodiment, said gel comprises 1.5 mg-20 mg vortioxetine pyroglutamateper ml, such as 2 mg-15 mg per ml, such as 3 mg-10 mg per ml. In oneembodiment, said gel comprises 0.1 M-1 M salt, such as 0.1 M-0.5 M salt,such as 0.1 M-0.3 M salt. In one embodiment, said gel comprises 0.5-20mg vortioxetine pyroglutamate pr ml and 0.1 M-1 M salt, such as 0.1M-0.5 M salt, such as 0.1 M-0.3 M salt. The amounts of vortioxetinepyroglutamate are indicated as free base. It is the experience of theinventors that the volume of the aqueous phase and the final gel areroughly similar when the gel comprises a therapeutically relevant dosein a therapeutically relevant volume.

The gel of the present invention is formed by mixing vortioxetinepyroglutamate, a salt and an aqueous solution, typically water. Gelformation is not sensitive to the mixing order, and vortioxetinepyroglutamate and/or the salt may be brought into solution prior tomixing with the other ingredients. In one embodiment, the inventionrelates to a gel formed by mixing vortioxetine pyroglutamate, a salt andwater. In one embodiment, vortioxetine pyroglutamate and a salt is mixedin an essentially dry state and an aqueous solution, such as water isadded to form the gel.

In one embodiment, the invention relates to a method of forming a gel,the method comprising mixing vortioxetine pyroglutamate, a salt and anaqueous solution, such as water.

The international patent applications published as WO 2011/023194 and WO2011/136376 disclose enteric coated formulations comprisingvortioxetine. In particular WO 2011/023194 discloses an experiment inwhich a radio guided capsule (Enterion™) was administered to subjects aspart of a 5-way crossover study (See example 1 of '194). In said studythe bioavailability and gastro intestinal (GI) tract adverse events werecompared between 20 mg vortioxetine HBr instant release (IR), 9 mgvortioxetine HBr IV, and 20 mg HBr solution released to the smallintestines (either the proximal bowel or the distal bowel). The fiftharm was without active compound.

The results showed unexpectedly that plasma concentration-time profilesare almost identical for 20 mg vortioxetine HBr IR formulation and 20 mgvortioxetine HBr solution released to the proximal or distal bowel. Putdifferently, the three formulations were bioequivalent. Moreover, theresults showed a markedly lower level of GI tract adverse events, inparticular a lower level of nausea and diarrhoea for the twoformulations released to the intestines compared to the IR formulation.In combination the results disclosed in WO 2011/023194 show thatvortioxetine released to the intestines (e.g. in an enteric formulation)is associated with a superior GI tract adverse event profile compared tovortioxetine administered in an IR formulation while delivering the sameplasma concentration, hence achieving the same therapeutic effect.

However, as shown in Example 17 vortioxetine HBr has inadequatebioavailability in an enteric coated tablet and therefore fails to beuseful as such. Example 17 is a 4-arm human study in healthy volunteerscomparing the plasma concentration-time profiles for 20 mg vortioxetineHBr administered as IR and in enteric coated formulations with releasesat pH 5.5, 6.0 and 7.0. pH in the stomach is very acidic and around1-1.5. pH increases sharply from the stomach into the small intestinesand increases from around 5.5 to 7.5 from the proximal to the distalparts [Adv Drug Deliv, 25, 3-14, 1997]. The release pH's investigatedfor the enteric coated formulations thus span release over the entirelength of the small intestines. As shown in FIG. 13, the enteric coatedformulations have a markedly decreased bioavailability with AUC_(0-72h)(Area Under the Curve) around 50% for the two enteric coatedformulations with release pH at 5.5 and 6.0 and around 10% for theenteric coated formulation with release pH of 7.0 (relative toAUC_(0-72h) for the IR tablet).

The enteric coated vortioxetine HBr tablet is therefore notbioequivalent to a vortioxetine HBr IR formulation and, as a consequencehereof, will not provide the same therapeutic effect. It cannot be ruledout that increasing the amount of vortioxetine HBr in an enteric coatedtablet could increase AUC; however for several reasons this may not bepossible or desirably. First, increasing the dose in an enteric coatedtablet may result in a different shape of the plasma concentration-timeprofile for which reason bioequivalence cannot be obtained. Second, eachpatient has different uptake of any given drug, and exposure of allpatients to high doses increases the risk of unexpected high andunwanted drug absorption and the safety concerns associated therewith.

The slopes of the rising parts of the plasma concentration-time profilesdepicted in FIG. 13 indicate that the dissolution rate for vortioxetineHBr in the intestines is markedly lower than that in the stomach. It issuggested that an inadequate dissolution rate of vortioxetine HBr atintestine relevant pH causes the compound not to be available forabsorption from the intestines into the plasma and therefore not to besuitable for administration in an enteric coated formulation.

The data reported in Example 18 shows the dissolution rate forvortioxetine HBr and vortioxetine pyroglutamate. The results show thatthe pyroglutamic acid salt of vortioxetine has a markedly higherdissolution rate compared to the HBr salt.

The experiment reported in Example 19 was conducted to test thehypothesis that a high dissolution rate for a vortioxetine salt isindicative for bioequivalence compared to a vortioxetine HBr IR tabletwhen said salt is provided in an enteric coated formulation. The studyis a 4-arm crossover study in dogs comparing the plasmaconcentration-time profiles for vortioxetine HBr administered in an IRformulation, vortioxetine HBr administered in an EC formulation;vortioxetine HBr administered as an oral solution, and vortioxetinepyroglutamate administered as an EC formulation. As seen from the datapresented in FIG. 14, the plasma concentration-time profiles forvortioxetine HBr in IR formulation and vortioxetine pyroglutamate in ECformulation are similar apart from a time-shift due to the delayedrelease. In comparison hereto, vortioxetine HBr in EC formulation has avery different profile with a much lower AUC. The initial slopes on theplasma concentration-time slopes in FIG. 14 also confirm that thedissolution rate for vortioxetine HBr in IR formulation and vortioxetinepyroglutamate in EC formulation is almost identical and much larger thanthat for vortioxetine HBr in EC formulation. The similarity between thedata obtained in Examples 17 and 19 serves to validate the resultsobtained in the dog study.

The data obtained in Example 19 shows that vortioxetine pyroglutamate inan EC formulation provides a plasma concentration-time profile which issimilar to that from vortioxetine HBr in an IR tablet. Based on thissimilarity it is concluded that a similar therapeutic effect is obtainedfrom two such formulations. In addition, the data disclosed in WO2011/023194 shows that if vortioxetine is released in the intestinesrather than in the stomach it is associated with a marked decrease ingastrointestinal adverse events. In the result, treatment of patientswith vortioxetine pyroglutamate salt in solid enteric coated formulationis expected to provide the same therapeutic effect and with a lowerlevel of gastrointestinal adverse events compared to treatment withvortioxetine HBr in a solid IR formulation. This is in contrast totreatment with vortioxetine HBr in enteric coated tablets which isassociated with a much lower absorption of the active ingredient, and aconsequent inferior therapeutic effect.

Vortioxetine HBr in an IR formulation is now approved in many majormarkets. A new formulation of vortioxetine which is bioequivalent to theexisting, approved IR formulation can in many countries rely on theregulatory safety and efficacy data on which the vortioxetine HBr IRformulation was approved for its own approval. Hence, bringing anenteric coated formulation of vortioxetine pyroglutamate to the marketcan be done without the need for lengthy and expensive clinical studies.

In one embodiment, the invention provides an enteric coated formulationcomprising vortioxetine pyroglutamate. In particular said entericformulation is solid and for oral administration. In one embodiment,said vortioxetine pyroglutamate is either of vortioxetine(DL)-pyroglutamate a-form, vortioxetine (L)-glutamate, vortioxetine(D)-pyroglutamate, vortioxetine (DL)-pyroglutamate mono hydrate, ormixtures thereof.

The total daily dose is typically between 1 and 50 mg vortioxetine (freebase), such as 1-10 mg, such as 5, 10, 15 or 20 mg.

In the present context, “enteric coated” is intended to indicate a pHsensitive coating which essentially does not allow vortioxetine to bereleased or dissolved in the stomach but essentially only in theintestines. A useful two-stage in vitro dissolution test is as follows.Equipment: Standard USP rotating paddle apparatus; paddle speed 75 rpm;37° C. First stage: A unit dose is exposed to 600 ml 0.1 M HCl for 2hours. Second stage: The unit dose is transferred to 900 ml TRIS buffer(0.6 M) with 0.3 w/w-% cetyl trimethylammonium bromide at pH at or above5.5 for 2 hours. Samples are withdrawn at suitable time points andanalysed for vortioxetine to determine the amount of vortioxetinereleased. The pH in the second stage may be adjusted to morespecifically determine where in the intestines the drug is released. Forexample, pH in the second stage may be 5.5, 6.0, 6.5, or 7.0. A unitdose typically comprises 1-50 mg vortioxetine. In one embodiment, if acoated formulation releases less than 10%, such as less than 5% of theunit dose in first stage, and the balance in second stage, said coatedformulation is said to be enteric coated. The use of TRIS buffer is notcritical, and other buffers may be used.

Enteric coating include pH sensitive polymers, such as polyacrylamides,phthalate derivatives such as acid phthalates of carbohydrates, amyloseacetate phthalate, cellulose acetate phthalate, other cellulose esterphthalates, cellulose ether phthalates, hydroxypropyl cellulosephthalate, hydroxypropylethyl cellulose phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, polyvinyl acetatephthalate, polyvinyl acetate hydrogen phthalate, sodium celluloseacetate phthalate, starch acid phthalate, styrene-maleic acid dibutylphthalate copolymer, styrene-maleic acid polyvinylacetate phthalatecopolymer, styrene and maleic acid copolymers, polyacrylic acidderivatives such as acrylic acid and acrylic ester copolymers,polymethacrylic acid and esters thereof, poly acrylic methacrylic acidcopolymers, shellac, and vinyl acetate and crotonic acid copolymers.

Anionic acrylic copolymers of methacrylic acid and methylmethacrylate orethyl acrylate are particularly useful pH dependent coating materials.Enteric coatings of this type are available from Degussa under thetradename Eudragit. Particularly useful are the products Eudragit L 30D-55, which comprises poly(methacrylic acid-co-ethyl acrylate) 1:1 witha molecular weight around 320,000 g/mol which provides dissolution at pHabove 5.5; Eudragit L100 which comprises poly(methacylic acid-co-methylmethacrylate) 1:1 with a molecular weight around 125,000 g/mol whichprovides dissolution at pH above 6.0; and Eudragit FS 30 D whichcomprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylicacid) 7:3:1 with a molecular weight around 280,00 g/mol which providesdissolution above pH 7.0. Thus, by applying either of the Eudragitpolymers in pure form or as mixtures thereof, it is possible to controlwhere in the intestine release takes place.

In one embodiment, a unit dose of the enteric coated formulation of thepresent invention is comprised in a single or a few tablets.Alternatively, a unit dose of the enteric coated formulation of thepresent invention is comprised in a multiple (such as e.g. 20-60) ofsmaller tablets. Said tablet(s) may be presented in a capsule whereinsaid capsule rather than the individual tablet(s) is/are enteric coated.

In one embodiment, the enteric coated formulation of the presentinvention is a multiparticulate formulation wherein a unit dose of theenteric coated formulation is comprised in a multiple of tablets eachtablet being enteric coated. This is often referred to as enteric coatedmini-tablets. This embodiment has the added advantage of being lesssensitive to damages to the coating which could result in dose dumping.

The enteric coated formulation of the present invention may be preparedby applying vortioxetine pyroglutamate on an inert core by drug-layeringtechniques, such as powder-coating, or by spraying a solution ofvortioxetine pyroglutamate and a suitable binder onto a core, e.g. in afluidized bed coater or a rotary mixer. The resulting cores aresubsequently coated with a suitable enteric coating. These particles maybe compressed into a tablet or presented in a capsule, as a powder or ina sachet.

Enteric coated tablets may be prepared in a number of ways available tothe skilled person. Tablets may be prepared by mixing vortioxetinepyroglutamate with ordinary adjuvants and/or diluents and subsequentlycompressing the mixture in a conventional tabletting machine. Examplesof adjuvants or diluents include PVP, PVP-VA co-polymers,microcrystalline cellulose, sodium starch glycolate, corn starch,mannitol, potato starch, talcum, magnesium stearate, gelatine, lactose,gums, croscarmellose sodium and the like. Any other adjuvants oradditives usually used for purposes such as colourings, flavourings,preservatives etc. may be used provided that they are compatible withthe other ingredients. The tablets obtained are subsequently coated witha suitable enteric coating, e.g. by spraying a solution comprising thecoating material onto the tablets.

In one embodiment, the invention provides an enteric formulationcomprising vortioxetine pyroglutamate in a tablet, which tablet iscoated with poly(methacrylic acid-co-ethyl acrylate) 1:1 with amolecular weight around 320,000 g/mol, or poly(methacylic acid-co-methylmethacrylate) 1:1 with a molecular weight around 125,000 g/mol, orpoly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1with a molecular weight around 280,000 g /mol. In the present context“molecular weight” is intended to indicate “Weight average molar mass”.

In one embodiment, the invention provides an enteric formulationcomprising vortioxetine pyroglutamate, mannitol, microcrystallinecellulose, sodium starch glycolate, hydroxypropyl cellulose andmagnesium stearate in a tablet, which tablet is coated withpoly(methacrylic acid-co-ethyl acrylate) 1:1 with a molecular weightaround 320,000 g/mol, or poly(methacylic acid-co-methyl methacrylate)1:1 with a molecular weight around 125,000 g/mol, or poly(methylacrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 with amolecular weight around 280,000 g/mol.

In one embodiment, the invention provides an enteric coated formulationcomprising vortioxetine pyroglutamate, microcrystalline cellulose,croscarmellose sodium and magnesium stearate in a tablet, which tabletis coated with poly(methacrylic acid-co-ethyl acrylate) 1:1 with amolecular weight around 320,000 g/mol, or poly(methacylic acid-co-methylmethacrylate) 1:1 with a molecular weight around 125,000 g/mol, orpoly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1with a molecular weight around 280,000 g/mol. In particular, saidformulation comprises 10% vortioxetine pyroglutamate, 86 w/w-%microcrystalline cellulose, 3 w/w-% croscarmellose sodium and 1 w/w-%magnesium stearate before coating. In particular, each tablet comprises1 mg vortioxetine (as free base).

Vortioxetine is approved by several health authorities for the treatmentof major depression or major depressive episode. As disclosed in e.g. WO03/029232 and WO 2007/144005 the pharmacological profile of vortioxetineis expected to also make the compound useful in the treatment of generalanxiety disorder; obsessive compulsive disorder (OCD), panic disorder;post-traumatic stress disorder; cognitive impairment; mild cognitiveimpairment (MCI); cognitive impairment associated with Alzheimer'sdisease, depression or schizophrenia (CIAS); and attention deficithyperactivity disorder (ADHD).

Cognitive deficits, cognitive impairment or cognitive dysfunctioninclude a decline in cognitive functions or cognitive domains, e.g.working memory, attention and vigilance, verbal learning and memory,visual learning and memory, reasoning and problem solving e.g. executivefunction, speed of processing and/or social cognition. In particular,cognitive deficits may indicate deficits in attention, disorganizedthinking, slow thinking, difficulty in understanding, poorconcentration, impairment of problem solving, poor memory, difficultiesin expressing thoughts and/or difficulties in integrating thoughts,feelings and behaviour, or difficulties in extinction of irrelevantthoughts. The terms “cognitive deficits”, “cognitive impairment” and“cognitive dysfunction” are intended to indicate the same and are usedinterchangeably.

In one embodiment, the invention relates to the use of vortioxetinepyroglutamate in the manufacture of a medicament for the treatment of adisease selected from major depressive disorder; major depressiveepisode; general anxiety disorder; obsessive compulsive disorder (OCD),panic disorder; post traumatic stress disorder; cognitive impairment;mild cognitive impairment (MCI); cognitive impairment associated withAlzheimer's disease, depression or schizophrenia (CIAS); and attentiondeficit hyperactivity disorder (ADHD).

In one embodiment, the invention relates to the use of vortioxetinepyroglutamate and a salt in the manufacture of a medicament for thetreatment of a disease selected from major depressive disorder; majordepressive episode; general anxiety disorder; obsessive compulsivedisorder (OCD), panic disorder; post traumatic stress disorder;cognitive impairment; mild cognitive impairment (MCI); cognitiveimpairment associated with Alzheimer's disease, depression,schizophrenia (CIAS); and attention deficit hyperactivity disorder(ADHD).

In one embodiment, the invention relates to vortioxetine pyroglutamatefor use in a method for the treatment of a disease selected from majordepressive disorder; major depressive episode; general anxiety disorder;obsessive compulsive disorder (OCD), panic disorder; post traumaticstress disorder; cognitive impairment; mild cognitive impairment (MCI);cognitive impairment associated with Alzheimer's disease, depression,schizophrenia (CIAS); and attention deficit hyperactivity disorder(ADHD).

In one embodiment, the invention relates to vortioxetine pyroglutamateand a salt for use in a method for the treatment of a disease selectedfrom major depressive disorder; major depressive episode; generalanxiety disorder; obsessive compulsive disorder (OCD), panic disorder;post traumatic stress disorder; cognitive impairment; mild cognitiveimpairment (MCI); cognitive impairment associated with Alzheimer'sdisease, depression, schizophrenia (CIAS); and attention deficithyperactivity disorder (ADHD).

In one embodiment, the invention relates to a method for the treatmentof a disease selected from major depressive disorder; major depressiveepisode; general anxiety disorder; obsessive compulsive disorder (OCD),panic disorder; post traumatic stress disorder; cognitive impairment;mild cognitive impairment (MCI); cognitive impairment associated withAlzheimer's disease, depression, schizophrenia (CIAS); and attentiondeficit hyperactivity disorder (ADHD), the method comprising theadministration of a therapeutically effective amount vortioxetinepyroglutamate to a patient in need thereof.

In one embodiment, the invention relates to a method for the treatmentof a disease selected from major depressive disorder; major depressiveepisode; general anxiety disorder; obsessive compulsive disorder (OCD),panic disorder; post traumatic stress disorder; cognitive impairment;mild cognitive impairment (MCI); cognitive impairment associated withAlzheimer's disease, depression, schizophrenia (CIAS); and attentiondeficit hyperactivity disorder (ADHD), the method comprising theadministration of a therapeutically effective amount of a gel comprisingvortioxetine pyroglutamate, a salt and water to a patient in needthereof.

In one embodiment, the invention relates to a method for the treatmentof a disease selected from major depressive disorder; major depressiveepisode; general anxiety disorder; obsessive compulsive disorder (OCD),panic disorder; post traumatic stress disorder; cognitive impairment;mild cognitive impairment (MCI); cognitive impairment associated withAlzheimer's disease, depression, schizophrenia (CIAS); and attentiondeficit hyperactivity disorder (ADHD), the method comprising theadministration of a therapeutically effective amount of a gel preparedby mixing a therapeutically effective amount of vortioxetinepyroglutamate, a salt and an aqueous solution, such as water, to apatient in need thereof.

In one embodiment, the patient treated according to the method of thepresent invention has been diagnosed with the indication for which saidpatient receives treatment.

In the present context, “treatment” or “treating” is intended toindicate the management and care of a patient for the purpose ofalleviating, arresting, partly arresting or delaying progress of theclinical manifestation of the disease, or curing the disease. Thepatient to be treated is preferably a mammal, in particular a humanbeing.

In the present context, “therapeutically effective amount” is intendedto indicate an amount of a compound which in a treatment comprising theadministration of said compound to a patient achieves a treatmenteffect.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law),regardless of any separately provided incorporation of particulardocuments made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. For example, the phrase “the compound”is to be understood as referring to various compounds of the inventionor particular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context(e.g., a composition described herein as comprising a particular elementshould be understood as also describing a composition consisting of thatelement, unless otherwise stated or clearly contradicted by context).

EXAMPLES

X-Ray powder diffractograms were measured on a PANalytical X′Pert PROX-Ray Diffractometer using CuK_(α1) radiation. The samples were measuredin reflection mode in the 2θ-range 5-40° using an X′celerator detector.

Differential Scanning calorimetry thermograms were obtained on equipmentfrom TA Instruments (DSC-Q2000) calibrated at 5° C./minute to give themelting point as onset value. Approximately 2 mg of the sample washeated at 5° C./minute in a closed pan with a pinhole in the lid andunder nitrogen flow.

Thermo gravimetric analysis thermograms used for measurement ofsolvent/water content of dried samples was performed using aTA-Instruments TGA-Q500. 1-10 mg sample was heated at 10° C./minute in aopen pan under nitrogen flow.

Dynamic Vapour Sorption spectra were obtained on equipment from SMSSystems (DVS Advantage). The change in mass (relative to the dry state)of a sample (10-20 mg) was determined as a function of the relativehumidity (P/P₀) at 25° C.

The gelling experiments were carried out in a 4 ml cylindrical vial withan inner diameter of approximately 1 cm.

Example 1 Vortioxetine (DL)-pyroglutamate Gel

To 5.5 mg vortioxetine (DL) pyroglutamate MH in a 4 mL vial was added asolution of potassium bromide in water (0.17 M, 1.0 mL) and theresulting mixture was shaken for 5 seconds. After standing for less than1 minute a clear gel was formed. The vial was left standing upside downfor more than 1 hour during which the gel properties of the gel weremaintained and the gel remained in the top (bottom) of the vial.

Example 2 Vortioxetine (DL)-pyroglutamate Gel

To 10.2 mg vortioxetine (DL)- pyroglutamate α-form in a 4 mL vial wasadded a solution of potassium bromide in water (0.23 M, 1.0 mL) and theresulting mixture was shaken for 5 seconds. After standing for less than1 minute a clear gel was formed. The vial was left standing upside downfor more than 1 hour during which the gel properties of the gel weremaintained and the gel remained in the top (bottom) of the vial.

Example 3 Vortioxetine (DL)-pyroglutamate Gel

To 6.2 mg vortioxetine (DL)-pyroglutamate MH in a 4 mL vial was addedwater (0.15 mL) and a solution of sodium bromide in water (0.307 M, 0.85mL, total 0.26 M) and the resulting mixture was shaken for 5 seconds.After standing for less than 1 minute a clear gel was formed. The vialwas left standing upside down for more than 30 minutes during which thegel properties of the gel were maintained and the gel remained in thetop (bottom) of the vial.

Example 4 Vortioxetine (DL)-pyroglutamate Gel

To 10.7 mg vortioxetine (DL)-pyroglutamate MH in a 4 mL vial was addedwater (0.35 mL) and a solution of sodium bromide in water (0.307 M, 0.65mL, total 0.20 M) and the resulting mixture was shaken for 5 seconds.After standing for less than 1 minute a clear gel was formed. The vialwas left to stand upside down for more than 1 hour during which the gelproperties of the gel were maintained and the gel remained in the top(bottom) of the vial.

Example 5 Vortioxetine (DL)-pyroglutamate Gel

To 0.80 g vortioxetine (DL)-pyroglutamate MH in a 250 mL round-bottomedflask was added a solution of sodium chloride in water (0.20 M, 100 mL)and the resulting mixture was shaken for 5 seconds. After standing for 2minute a clear gel was formed. The flask was left to stand upside downfor more than 30 minutes during which the gel properties were maintainedand the gel remained in the top (bottom) of the flask.

Example 6 Vortioxetine (DL)-pyroglutamate Gel

To 8.0 mg vortioxetine (DL)-pyroglutamat MH in a 4 mL vial was addedwater (0.15 mL) and a solution of sodium chloride in water (0.31 M, 0.85mL, total 0.26 M) and the resulting mixture was shaken for 5 seconds.After standing for 6 minute a clear gel was formed. The vial was left tostand upside down for more than 1 hour during which the gel propertiesof the gel were maintained and the gel remained in the top (bottom) ofthe vial.

Example 7 Vortioxetine (DL)-pyroglutamate Gel

To 11.2 mg vortioxetine (DL)-pyroglutamate MH in a 4 mL vial was addedwater (0.20 mL) and a solution of sodium chloride in water (0.31 M, 0.80mL, total 0.25 M) and the resulting mixture was shaken for 5 seconds.After standing for 5 minute a clear gel was formed. The vial was left tostand upside down for more than 30 minutes during which the gelproperties of the gel were maintained and the gel remained in the top(bottom) of the vial.

Example 8 Vortioxetine (DL)-pyroglutamate Gel

To 7.6 mg vortioxetine (L)-pyroglutamate in a 4 mL vial was added asolution of sodium bromide in water (0.18 M, 1.0 mL) and the resultingmixture was shaken for 5 seconds. After standing for less than 1 minutea clear gel was formed. The vial was left to stand upside down for morethan 30 minutes during which the gel properties of the gel weremaintained and the gel remained in the top (bottom) of the vial.

Example 9 Vortioxetine (DL)-pyroglutamate Gel

14 mg vortioxetine (DL)-pyroglutamate MH in a 4 mL vial was added sodiumchloride (26 mg) and water (2.0 mL) and the resulting mixture was shakenfor 5 seconds. After standing for less than 1 minute gel was formed. Thevial was left to stand upside down for more than 10 minutes during whichthe gel properties of the gel were maintained and the gel remained inthe top (bottom) of the vial.

Example 10 Preparation of Vortioxetine (L)-pyroglutamate

Vortioxetine (2.98 g) was dissolved in 2-propanol (15 mL) at 60° C. Tothis stirred reaction mixture was drop-wise added a warm solution (60°C.) of L-pyroglutamic acid (1.29 g) in 2-propanol (15 mL). The reactionwas cooled to room temperature over a 2 hour period and then cooled to0-5° C. for 1.5 h prior to filtration. Vortioxetine (L)-pyroglutamatewas isolated by filtration. The filter cake was washed with 2-propanol(2×5 mL) and dried under vacuum overnight to yield 4.09 g (96% yield).

¹H NMR (DMSO-d₆): 7.65 (s, 1H), 7.33 (d, 1H), 7.24 (s, 1H), 7.10 (m,3H), 6.93 (dd, 1H), 6.40 (d, 1H), 3.87 (dd, 1H), 3.10 (bs, 8H), 2.32 (s,3 H), 2.24 (s, 3H), 2.23 (mp, 1H), 2.08 (mp, 2H), 1.95 (mp, 1H).

Example 11 Characterization of Vortioxetine (L)-pyroglutamate

Elemental analysis of the product obtained in Example 10 gave thefollowing results: 63.5% C, 6.95% H, 9.44% N, Karl Fisher (KF): 1.6%water (Theory corrected for 1.6% water: 63.58% C, 6.91% H, 9.67% N).

XRPD spectrum of the product obtained in Example 10 is shown in FIG. 1.The spectrum shows that the product is essentially in a crystallineform. Vortioxetine (L)-pyroglutamate has characteristic XRPD reflectionsat 10.72, 12.14, 16.22 and 18.59 (° 2θ); such as 10.72, 12.14, 16.05,16.22, 17.53, 17.70, 18.45 and 18.59 (° 2θ), such as 7.02, 10.72, 12.14,14.45, 14.61, 15.56, 16.05, 16.22, 17.53, 17.70, 18.45 and 18.59 (° 2θ).All values are ±0.1 ° 2θ.

TGA thermogram of the product obtained in Example 10 is shown in FIG. 2.An initial loss of water is followed by a small weight loss which isprobably from solvent trapped in the crystals released during melting.

DSC thermogram of the product obtained in Example 10 is shown in FIG. 3.After an initial loss of water, there is a sharp melting peak at 138.9°C. (onset value).

DVS spectrum of the product obtained in Example 10 is shown in FIG. 4.The sample contained 4% water when the measurement was initiated.Further 2.7% is gradually absorbed as the humidity increases up to 95%Relative Humidity. All water is gradually released as the humidity islowered to 0% RH. It may be noted that the sample appears to haveabsorbed water between the KF water content determination and the DVSmeasurement.

To 500 mg vortioxetine (L)-pyroglutamate was added 900 μl water at 21°C. The viscous solution containing weak precipitation was centrifuged,filtered and the concentration of the supernatant was determined by HPLCafter dilution.

HPLC Method:

Column: X-Bridge C18, 150 * 4.6 mm ID, 3.5 μm or equivalent MobilePhase: 25 mM phosphatebuffer pH 6.0/MeOH (35/65) Column Temperature: 45°C. Detector: UV at 225 nm Flow: 1 ml/min Injection volume: 10 μl Time ofAnalysis: 15 minutes The results showed that vortioxetine(L)-pyroglutamate has a solubility of 225 mg/ml.

Example 12 Preparation of Vortioxetine (DL)-pyroglutamate MH

Vortioxetine HBr salt (750 g), (DL)-pyroglutamic acid (250 g) and methyltetrahydrofuran (10 L) were mixed in a reactor. To this mixture wasadded sodium hydroxide solution (1 M , 3.4 L) and the mixture was thenheat to approximately 40° C. Once a clear solution was formed, thestirring was stopped and the reaction was allowed to stand to allow thephases to separate. The organic phase was retained and the water phasewas discarded. The organic phase was washed with water (3 L) andfollowed by sodium hydroxide solution (1 M , 2 L) and stirred for 30minutes after which the stirring was stopped and the reaction wasallowed to stand to allow the phases to separate. The organic phase wasretained and the water phase was discarded. (DL)-pyrogultamic acid(0.250 kg) was added to the organic phase and then reduced in volume bydistillation (approx 5.3 L removed by distillation). The mixture wasallowed to cool and the product isolated by filtration. The filter cakewas washed with cold methyl tetrahydrofuran (2.5 L) and dried underreduce pressure at 40° C. to give the desired vortioxetine(DL)-pyrogultamate MH salt (705 g). The initial addition of(DL)-pyroglutamic acid was an error. This error has no impact on theoutcome of the synthesis.

Example 13 Characterization of Vortioxetine (DL)-pyroglutamate MH

Elemental analysis of the product obtained in Example 12 gave thefollowing results: 61.94% C, 6.99% H, 9.40% N (theory for a monohydrate:62.00% C, 7.01% H, 9.43% N)

XRPD spectrum of the product obtained in example 12 is shown in FIG. 5.The spectrum shows that the product is essentially in a crystallineform. Vortioxetine (DL)-pyroglutamate MH has characteristic XRPDreflections at 6.16, 9.25, 17.68 and 18.12 (° 2θ), such as at 6.16,9.25, 14.61, 15.02, 15.88, 16.33, 17.68 and 18.12 (° 2θ), such as at6.16, 9.25, 9.38, 12.10, 14.03, 14.61, 15.02, 15.88, 16.33, 16.91, 17.68and 18.12 (° 2θ). All values are ±0.1 ° 2θ.

DSC thermogram of the product obtained in Example 12 is shown in FIG. 6.After desolvation (1^(st) broad peak at ˜95° C.) the alpha form isformed, which then melts.

The two-step weight loss corresponding to desolvation can also beidentified in the TGA thermogram of the product obtained in example 12shown in FIG. 7.

DVS spectrum of the product obtained in example 12 is shown in FIG. 8.Vortioxetine (DL)-pyroglutamate MH is not hygroscopic up to 80% relativehumidity at 25° C. At 90% relative humidity some water is absorbed andat 95% relative humidity it is hygroscopic. Equilibrium is not reachedthus more than 10% is absorbed and a sample stored at 95% relativehumidity for prolonged period of time becomes liquid.

200 mg vortioxetine (DL)-pyroglutamate MH was dissolved in 200 μl waterat room temperature. Due to the changes in volume induced, theconcentration was calculated to 278 mg/ml. From this a solubility of atleast 278 mg/ml is determined.

Example 14 Preparation of Vortioxetine (DL)-pyroglutamate α-form

Vortioxetine HBr salt (750 g) and methyl tetrahydrofuran (10 L) weremixed in a reactor. To this mixture was added sodium hydroxide solution(1 M , 3.4 L) and the mixture was then heated to approximately 40° C. .Once a clear solution was formed the stirring was stopped and thereaction was allowed to stand to allow the phases to separate. Theorganic phase was retained and the water phase was discarded. Organicphase was washed with water (3 L) and (DL)- pyrogultamic acid (0.250 kg)was added to the organic phase and then reduced in volume bydistillation (approximately 7 L removed by distillation). Additionalmethyl tetrahydrofuran was added (2 L) and distilled a little furtheruntil the reaction mixture was approximately 77° C. The mixture was thencooled down to approximately 10° C. and the product isolated byfiltration. The filter cake was washed with cold methyl tetrahydrofuran(2 L) and dried under reduced pressure to give the desired vortioxetine(DL)-pyrogultamate a-form salt (807 g).

Example 15 Characterisation of Vortioxetine (DL)-pyroglutamate α-form

Elemental analysis of the product obtained in Example 14 gave thefollowing results: 64.52% C, 6.83% H, 9.73% N (Theory: 64.61% C, 6.84%H, 9.83% N).

XRPD spectrum of the product obtained in Example 14 I shown in FIG. 9.The spectrum shows that vortioxetine (DL)pyroglutamate α-form isessentially in a crystalline form. Vortioxetine (DL)pyroglutamate α-formhas characteristic XRPD reflections at 14.27, 15.75, 17.06 and 18.59 (°2θ), such as at 7.42, 10.78, 13.58, 14.27, 14.60, 15.75, 17.06 and18.59(° 2θ), such as at 7.42, 10.78, 13.58, 13.99, 14.27, 14.60, 15.75,15.90, 16.89, 17.06, 17.87 and 18.59 (° 2θ). All values are ±0.1 ° 2θ.

DSC thermogram of the product obtained in Example 14 is shown in FIG.10. Vortioxetine (DL)pyroglutamate a-form has a melting point 178.2° C.(onset value).

TGA thermogram of the product obtained in Example 14 is shown in FIG.11. As evidenced by the data Vortioxetine (DL)pyroglutamate a-form hasno weight loss before the melting point.

DVS spectrum of the product obtained in example 14 is shown in FIG. 12.The spectrum shows that show that vortioxetine (DL)pyroglutamate α-formis not hygroscopic. Less than 0.3% was absorbed up to 95% relativehumidity.

200 mg vortioxetine (DL)-pyroglutamate a-form was dissolved in 200 μlwater at room temperature. Due to the changes in volume induced, theconcentration was calculated to 278 mg/ml. From this a solubility of atleast 278 mg/ml is determined.

Example 16 Preparation of Vortioxetine (DL)-pyroglutamate α-form

Vortioxetine HBr salt (750 g), methyl tetrahydrofuran (10.5 L) and water(3 L) were stirred in a reactor. To this mixture was added sodiumhydroxide solution (27.7%, 3.8 L) and the mixture was heat toapproximately 70° C. Once a clear solution was formed the stirring wasstopped and the reaction was allowed to stand to allow the phases toseparate. The organic phase was retained and the water phase wasdiscarded. DL-pyrogultamic acid (0.263 kg) was added to the organicphase which was then reduced in volume by distillation (approx 8 Lremoved by distillation). The mixture was then cooled down toapproximately 10° C. and the product isolated by filtration. The filtercake was washed with cold methyl tetrahydrofuran (2 L) and dried underreduce pressure to give the desired vortioxetine (DL)-pyrogultamateα-form salt (803 g). The crystalline form was confirmed by XRPD.

Example 17 Clinical Study with Vortioxetine HBr in Enteric CoatedFormulation

Three different enteric coated formulations were prepared with identicalcores a shown below

Dose (mg) 1 Tablet mass (mg) 15 % w/w Vortioxetine HBr 8.47Microcrystalline cellulose 15.00 Mannitol 69.53 Hydroxypropylcellulose3.0 Sodium starch glycolate 3.0 (Type A) Magnesium stearate 1.0 Sum 100

Vortioxetine HBr (particle size distribution X₁₀ 1.9 μm; X₅₀ 9.3 μm; X₉₀49 μm; X₉₉ 150 μm, all volume mean diameter) was mixed with mannitol,microcrystalline cellulose and hydroxypropylcellulose in a fluid bed andgranulation water was added, and the mixture was allowed to granulateupon which the granules were dried and sieved. The granules were mixedwith microcrystalline cellulose and sodium starch glycolate (type A) ina blender together with magnesium stearate. The resulting granules werepressed into tablet cores using 3 mm punches.

The core tablets were subsequently coated with a sub-coating of OpadryPink (3.5% w/w) and three different enteric coatings to achieve releaseat pH above 5.5, pH above 6.0 and pH above 7.0. The coating suspensionsare indicated below. Eudragite L 30 D-55, Eudragite L100 and EudragiteFS 30 D were applied corresponding to 15.3 mg/cm², 18 mg/cm² and 11mg/cm², respectively.

The sub-coat is applied to make the mini-tablet more spherical toachieve a more homogeneous coating with the enteric polymer. Opadry Pinkis a coloured coating comprising hypromellose type 2910, titaniumdioxide, polyethylene glycol 400 and iron oxide red. The compositions ofEudragite L 30 D-55, Eudragite L100 and Eudragite FS 30 D are discussedabove. PlasAcryl T20 is a commercially available plasticizer comprisingglycerol monostearate, triethyl cistrate and polysorbate 80.

% w/w L 30 D-55 L 100 FS 30 D Release at Release at Release at pH abovepH above pH above Opadry 5.5 6.0 7.0 Opadry 15 Eudragit L 30 D-55 57.9Eudragit L100 9.95 Eudragit FS 30 D 60.6 Triethyl citrate 0.9 4.98 Talc4.98 Glycerol 0.72 monostearate 1N NH₃ 5.6 PlasAcryl T20 8.7 9.1 Water85 32.5 74.49 29.58 Total (%) 100 100 100 100

Capsules containing mini-tablets as prepared above (20 mg vortioxetinefree base) were tested together with 20 mg IR tablet (commercial,encapsulated) in a single-centre, randomised, double-blind, 4-waycrossover, single-dose study in healthy women. Each dosing was separatedby at least 21 days wash-out period. Following dosing blood samples weredrawn at pre-determined points up to 72 hours for analysis ofvortioxetine plasma levels.

The commercial 20 mg tablet comprises mannitol, microcrystallinecellulose, hydroxypropylcellulose, sodium starch glycolate, magnesiumstearate and a film coating which consists of hypromellose, titaniumdioxide, polyethylene glycol 400 and colorant.

The table below gives the mean pharmacokinetic data for each of the fourarms, and the plasma concentration-time profiles are shown in FIG. 17.

20 mg enteric 20 mg enteric 20 mg enteric coated 20 mg IR coated (pH5.5) coated (pH 6.0) (pH 7.0) N = 37 N = 36 N = 38 N = 35 AUC_(0-72 h)(ng 366 201 214 46.8 h/ml) C_(max) (ng/ml) 9.84 4.37 4.77 0.797

Relevant statistical data are shown below

Ratio and 90% CI of the Parameter Comparison (Test v Reference) Ratio(Test:Reference) AUC_(0-72 h) 20 mg EC pH 5.5 v 20 mg IR 0.555 (0.505,0.610) (ng h/ml) 20 mg EC pH 6.0 v 20 mg IR 0.599 (0.556, 0.646) 20 mgEC pH 7.0 v 20 mg IR 0.0991 (0.0802, 0.122) C_(max) (ng/ml) 20 mg EC pH5.5 v 20 mg IR 0.404 (0.330, 0.494) 20 mg EC pH 6.0 v 20 mg IR 0.484(0.444, 0.528) 20 mg EC pH 7.0 v 20 mg IR 0.0497 (0.0372, 0.0664) CI:Confidence Interval.

Bioequivalence typically requires the ratio to be between 0.8 and 1.15.

Example 18 Intrinsic Dissolution Rate for Vortioxetine Salts

The intrinsic dissolution rate (IDR) is expressed as mg vortioxetinedissolved per cm² surface per min. The intrinsic dissolution rate ismeasured using the “spinning-disc method” (μDISS Profiler Instrumentfrom Pion Instruments).

In order to define the surface from which the test compound dissolves,miniaturized disks of compacted pure test compound are made (10 mg). Thedisk holding the test compound is inserted into a Teflon cup containingan imbedded magnet. The cup is inserted into a vial containing 20 mldissolution medium (37° C./200 RPM). The dissolved test compound ismeasured by a fibre optic detection system (200-400 nm). Theconcentration is determined by comparison with a standard solution andthe calculated amount of test compound released (as free base) persurface area is plotted versus time. The slope gives the intrinsicdissolution rate. The measurements are performed in duplicate. Thedissolution medium was 50 mM Tris at pH 6.8. Vortioxetine HBr β-form isdefined in WO 2007/144005 (see e.g. example 4c and 4d).

IDR (mean of 2 determinations Salt (mg/cm2/min) HBr (β form) 0.10L-Pyroglutamate 14.9 DL-Pyroglutamate 14.7

Example 19 Pre-clinical Study with Vortioxetine Salts in Enteric CoatedFormulations in Dogs

Two different enteric coated vortioxetine formulations were compared tothe commercial IR tablet and a solution of vortioxetine. The firstenteric coated formulation comprised vortioxetine HBr, released at pHabove 5.5 and was prepared as indicated in Example 17. The secondenteric coated formulation comprised vortioxetine (DL)-pyroglutamatea-form with a core composition as indicated below

Dose (mg) 1 Tablet mass (mg) 15 % w/w Vortioxetine 9.55 puroglutamateMicrocrystalline cellulose 86.45 Croscarmellose sodium 3.0 Magnesiumstearate 1.0 Sum 100

The tablet cores were prepared by direct compression. A pre-blend wasprepared by mixing vortioxetine pyroglutamate with microcrystallinecellulose in a 1:1 ratio. The remaining microcrystalline cellulose andcroscarmellose sodium were added in a blender. Finally, magnesiumstearate was added. Tablet cores were pressed using 3 mm punches.

The core tablets were sub-coated with Opadry Pink (20% w/w) beforecoating with Eudragite L30 D-55 to achieve a release pH above 5.5.Coating suspensions are indicated below

% w/w Opadry L 30 D-55 Eudragit L 30 D-55 57.9 Opadry Pink 15 Triethylcitrate 0.9 PlasAcryl T20 8.7 Water 85 32.5 Total (%) 100 100The protocol used for the dog in vivo studies was approved by theinstitutional ethics committee in accordance with Danish law regulatingexperiments on animals and in compliance with EU directive 2010/63/EU,and the NIH guidelines on animal welfare. Male beagle dogs was used forthe in a non-randomised cross-over design, with an average weight of9.23-11.2 kg. The animals was fed twice daily with approximately 240grams of Certified Dog Diet daily (Beijing Vital Keao Feed Co., Ltd.Beijing, P. R. China) and kept in rooms with controlled and monitoredfor relative humidity (40% to 70% RH) and temperature from 18° C. to 26°with 10 to 20 air changes/hour. The room was on a 12-hour light/darkcycle except when interruptions were necessitated by study activities.

Before administration of the formulations the animals was be fed theafternoon (at 3:30 to 4:00 pm) prior to the day of dosing and theremaining food was removed in the morning. Food was withheld until10-hour post-dose. The animals had free access to drinking waterthrough-out the study. 30 min before administration of the oralformulation the animals was injected intramuscular with 6 μg/kg ofpentagastrin in a saline solution. The animals were administered perorally with 20 mg vortioxitine as either of the three tablets or an oralsolution containing 1 mg/mL of vortioxitin solubilized in 5%2-hydroxypropyl-β-cyclodextrin. Immediately following capsule/tabletadministration, water was given to the mouth to the animals at the dosevolume of about 10 mL /animal to help capsule swallowing.

Blood samples were collected following oral administration vortioxetineat pre-dose, 5, 15, and 30 min as well as after 1, 2, 4, 6, 8, 12 and 24hours for analysis of vortioxetine levels in plasma. The plasmaconcentration-time profiles are depicted in FIG. 14, and the table belowgives the mean pharmacokinetic data.

20 mg 20 mg 20 mg pyroglutamate HBr oral HBr IR 20 mg HBr EC EC solutionN = 4 N = 4 N = 4 N = 4 AUC_(0-24 h) (ng 553 245 481 631 h/ml) C_(max)(ng/ml) 49.9 19.4 45.5 58.6

Relevant statistical data are shown in the table below

Ratio and 90% CI of the Ratio Parameter Comparison (Test v Reference)(Test:Reference) AUC_(0-72 h) 20 mg IR v 20 mg HBr EC 0.44 (0.30, 0.65)(ng h/ml) 20 mg IR v 20 mg pyroglutamate EC 0.83 (0.65, 1.06) 20 mg IR v20 mg solution 1.17 (1.05, 1.30) C_(max) (ng/ml) 20 mg IR v 20 mg HBr EC0.39 (0.34, 0.45) 20 mg IR v 20 mg pyroglutamate EC 0.84 (0.51, 1.37) 20mg IR v 20 mg solution 1.16 (0.92, 1.44)

1. Vortioxetine pyroglutamate.
 2. The compound according to claim 1,wherein the compound is selected from the group consisting ofvortioxetine (L)-pyroglutamate, vortioxetine (D)-pyroglutamate andvortioxetine (DL)-pyroglutamate.
 3. The compound according to claim 1,wherein the compound is vortioxetine (L)-pyroglutamate or vortioxetine(D)-pyroglutamate in crystalline form with XRPD reflections at 10.72,12.14, 16.22 and 18.59 (° 2θ) (±0.1 ° 2θ).
 4. The compound according toclaim 1, wherein the compound is vortioxetine (DL)-pyroglutamatemonohydrate in crystalline form with XRPD reflections at 6.16, 9.25,17.68 and 18.12 (° 2θ) (±0.1 ° 2θ).
 5. The compound according to claim1, wherein the compound is vortioxetine (DL)-pyroglutamate a-form incrystalline form with XRPD reflections at 14.27, 15.75, 17.06 and 18.59(° 2θ) (±0.1 ° 2θ).
 6. A pharmaceutical composition, comprising thecompound of claim 1 together with at least one pharmaceuticallyacceptable carrier or diluent.
 7. A gelable pharmaceutical composition,comprising the compound of claim 1 and a salt.
 8. A gel, comprising thecompound of claim 1, a salt and water.
 9. A solid pharmaceuticalcomposition for oral administration, comprising the compound of claim 1and an enteric coating.
 10. A method for preparing a gel, said methodcomprising mixing the compound of claim 1, a salt and an aqueoussolution.
 11. A method for the treatment of a disease selected frommajor depressive disorder; major depressive episode; general anxietydisorder; obsessive compulsive disorder (OCD), panic disorder; posttraumatic stress disorder; cognitive impairment; mild cognitiveimpairment (MCI); cognitive impairment associated with Alzheimer'sdisease, depression, schizophrenia (CIAS); and attention deficithyperactivity disorder (ADHD), the method comprising the administrationof a therapeutically effective amount of the compound of claim 1 to apatient in need thereof.
 12. A method for the treatment of a diseaseselected from major depressive disorder; major depressive episode;general anxiety disorder; obsessive compulsive disorder (OCD), panicdisorder; post traumatic stress disorder; cognitive impairment; mildcognitive impairment (MCI); cognitive impairment associated withAlzheimer's disease, depression, schizophrenia (CIAS); and attentiondeficit hyperactivity disorder (ADHD), the method comprising theadministration of a therapeutically effective amount of a gel comprisingthe compound of claim 1, a salt and water, to a patient in need thereof.13. A method for the treatment of a disease selected from majordepressive disorder; major depressive episode; general anxiety disorder;obsessive compulsive disorder (OCD), panic disorder; post traumaticstress disorder; cognitive impairment; mild cognitive impairment (MCI);cognitive impairment associated with Alzheimer's disease, depression,schizophrenia (CIAS); and attention deficit hyperactivity disorder(ADHD), the method comprising the administration of a therapeuticallyeffective amount of a gel to a patient in need thereof, wherein said gelis prepared by mixing the compound of claim 1, a salt and water.